Gastrointestinal Tract Infections

Ch. 23

Gastroenteritis

Syndrome characterized by gastrointestinal symptoms including nausea, vomiting, diarrhea, and abdominal discomfort

Diarrhea

Abnormal fecal discharge characterized by frequent/fluid stool

Usually resulting form disease of the small intestine

Involves increased fluid and electrolyte loss

Dysentery

An inflammatory disorder of the GI tract often associated with blood and pus in the feces

Accompanied by symptoms of pain, fever, abdominal cramps

Usually resulting from disease of the large intestine

Enterocolitis

Inflammation involving the mucosa of both the small and large intestine

For a GI infection to occur, a pathogen must do what?

Be ingested in sufficient numbers

Elude the host defenses in the upper tract

Reach the intestines

What host defenses provide protection against GI infections?

Lysozyme

Acid pH

Mucus

Bile

IgA

Peyer’s patches

Peristalsis

What is the most common outcome of GI tract infections?

diarrhea

In “resource poor” countries, what is the major cause of mortality in children?

diarrheal disease

What are the 6 different distinct pathotypes of *E. coli*?

EPEC – enteropathogenic *E. coli*

ETEC – enterotoxigenic *E. coli*

EHEC – shiga-toxin producing *E. coli* (aka STEC or VTEC)

EIEC – enteroinvasive *E. coli*

EAEC – enteroaggregative *E. coli*

DAEC – diffusely aggregative *E. coli*

*E. coli*

Gram negative rod

Many virulence factors – specifically adhesin and exotoxins

EPEC – enteropathogenic *E. coli*

Small intestine

Primarily occurs in children

What virulence factors do EPEC contain?

Adherence factor plasmid

Bundle-forming pili (BFP)

Intimin (adhesin)

Translocated intimin receptor (Tir)

What is the pathogenesis of EPEC?

Plasmid-mediatedA/E histopathology, with disruption of normal microvillus structure resulting in malabsorptionand diarrhea

How can we diagnose EPEC?

Characteristic adherence to HEp-2 or HeLa cells

Probes and amplification assays developed for the plasmid- encoded bundle-forming

Pili and gene targets on the “locus of enterocyte effacement” pathogenicity

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ETEC – enterotoxigenic *E. coli*

Small intestine

Gram negative rod, **FERMENTS LACTOSE**

Traveler’s diarrhea; infant diarrhea in developing countries

Watery diarrhea, vomiting, cramps, nausea, low-grade fever

What is the pathogenesis of ETEC?

Plasmid-mediated, ST and LT enterotoxins that stimulate hypersecretion of fluids and electrolytes

What are the two toxins ETEC produces?

Heat-stable toxins (STa and STb)

Heat-labile toxins (LT-I and LT-II)

STa

Monomeric peptide 

Binds to transmembrane guanylate cyclase C receptor 

Increases cGMP → hypersecretion of fluids/inhibition of fluid absorption

LT-I

Very similar to cholera toxin

1 A subunit & 5 B subunits

B subunits bind to GM1 gangliosides → internalization of A

A subunit interacts with Gs → dysregulation of adenylate cyclase

What is the MOA of ETEC LT-1?

5 B subunits bind to GM1 receptors on intestinal epithelial cells → A (active) subunit is internalized → Interacts w/ G proteins that regulate adenylate cyclase → Increase cAMP → Hypersecretion of water & electrolytes → Adhere to the mucosal layer to avoid flushing

How can we diagnose ETEC?

Plasmid-mediated, ST and LT enterotoxins that stimulate hypersecretion of fluids and electrolytes

EHEC – shiga-toxin producing *E. coli* (aka STEC or VTEC)

Large intestine (attaches to mucosa)

Initial watery diarrhea → grossly bloody diarrhea (hemorrhagic colitis) w/ abdominal cramps

Little/No fever

May progress to hemolytic uremic syndrome

Cattle major reservoirs

Can survive in soil for months

What toxin does EHEC/STEC produce?

Stx1 (identical to Shiga toxin produced by *S.dysenteriae*)

What is the MOA of Stx1/2 toxin?

stimulates inflammation which enhances expression of Gb3

B subunits bind specific glycolipid (Gb3)

A subunit is internalized → cleaved

A1 binds 28s rRNA → stops protein synthesis

Hemorrhagic colitis (HC)

Destruction of mucosa

Results in subsequent hemorrhage

Can be followed by HUS

Hemorrhagic uremic syndrome (HUS)

Receptors on renal epithelium for toxins

Acute renal failure (children), anemia/thrombocytopenia, possible neurological complications

What is the pathogenesis of EHEC/STEC?

STEC evolved from EPEC

A/E lesions with destruction of intestinal microvilli, resulting in decreased absorption

Pathology mediated by cytotoxic Shiga toxins (Stx1, Stx2), which disrupt

protein synthesis

How can we diagnose EHEC/STEC?

Screen for O157:H7 with sorbitol-MacConkey agar → confirm by serotyping

Immunoassays (ELISA,latex agglutination) for detection of the Stx toxins in stool specimens and cultured bacteria

DNA amplification assays developed for Stx genes

EIEC – enteroinvasive *E. coli*

Large intestine; invade & destroy colonic epithelium

Rare in developing and developed countries

Fever, cramping, watery diarrhea

May progress to dysentery w/ scant bloody stools

EAEC – enteroaggregative *E. coli*

Small intestine

Infant diarrhea in developing & probably developed countries

Traveler’s diarrhea

Persistent watery diarrhea, vomiting, dehydration, low-grade fever

What is the pathogenesis of EAEC?

Plasmid-mediated aggregative adherence of rods (“stacked bricks”) w/ shortening of microvilli, mononuclear infiltration, and hemorrhage; decreased fluid absorption

How can we diagnose EAEC?

Characteristic adherence to HEp-2 cells

DNA probe and amplification assays developed for conserved plasmid

DAEC – diffusely aggregative *E. coli*

Produce an alpha hemolysin & cytotoxic necrotizing factor 1

What types of *E. coli* are the most important contributors to global incidence of diarrheal disease?

\
A. DAEC

B. EAEC

C. EHEC

D. EIEC 

E. EPEC

F. ETEC

E. EPEC

F. ETEC

What types of *E. coli* both cause bloody diarrhea?

\
A. DAEC

B. EAEC

C. EHEC

D. EIEC 

E. EPEC

F. ETEC

C. EHEC

D. EIEC 

What type of *E. coli* is the most common cause of acute renal failure in children in the UK and USA?

\
A. DAEC

B. EAEC

C. EHEC

D. EIEC 

E. EPEC

F. ETEC

C. EHEC

What marker on EHEC is most commonly associated with HUS?

O157:H7

What type of treatment is NOT indicated for *E. coli* diarrhea?

Antibiotic therapy

What types of *E. coli* can result from ingestion of food and unpasteurized milk?

\
A. DAEC

B. EAEC

C. EHEC

D. EIEC 

E. EPEC

F. ETEC

C. EHEC

D. EIEC 

Salmonella

Gram - rods; doesn’t ferment lactose

2nd most common cause of food associated diarrhea

Human infection: *Salmonella enterica* Typhi and *Salmonella enterica* paratyphi A, B, C

Cause Typhoid fever and paratyphoid fever (both enteric fever)

How are we infected with *Salmonella*?

Ingestion of contaminated food or fecal-oral

Most common sources are poultry, eggs, dairy products

What is the pathogenesis of *Salmonella*?

Attaches to mucosa of small intestine → invade microfold (M) cells in Peyer patches (also invades enterocytes) → bacteria remain in endocytic vacuoles → released into blood or lymphatic circulation → type III secretion system injects proteins into host cell → inflammatory response confines infection to GI tract → mediates release of prostaglandins → stimulates cAMP & active fluid secretion

How does *Salmonella* present?

Symptoms appear 6-48 hrs after ingestion

Nausea, vomiting, and **nonbloody** diarrhea

Fever, abdominal cramps, myalgia, headache are also common

Colonic involvement can be seen in acute forms of the disease

Serious infections with *Salmonella* can cause what?

Sepsis   

How can we diagnose Salmonella?

Culture on selective media: MacConkey agar (doesn’t ferment lactose)

Classic Ab detection – Widal test (Agglutination assay; detects Ab of LPS (O antigen) & flagella (H antigen))

How can we treat Salmonella?

Fluid & electrolyte replacement 

Antibiotics discouraged (used only for invasive disease)

Antidiarrheal medicine 

*Campylobacter jejuni*

S-shaped Gram - rod

Most common causes of bacterial gastroenteritis 

Microaerophilic/thermophilic

Can result in Guillain-Barre syndrome 

What is the pathogenesis of *C. jejuni*?

Plethora of adhesin, enzymes & enterotoxins

GI disease characterized by histological damage to mucosal surface of jejunum, ileum, & colon

Mucosal surface appears ulcerated, edematous, bloody

Guillain-Barre Syndrome

immune disorder of peripheral nervous system; caused by *C. jejuni*

How is *C. jejuni* transmitted?

Reservoir in cattle, sheep rodents, poultry, wild birds

Acquired through consumption of contaminated food

Most common cause of bacterial diarrheal illness in USA

How does *C. jejuni* present?

Acute enteritis w/ diarrhea, fever, severe abdominal pain (stools may be **bloody)**

Manifestations can include acute colitis, abdominal pain (can mimic acute appendicitis)

*Campylobacter*

Clinically similar to S*almonella* & *Shigella* presentations

Ulceration & inflamed bleeding mucosal surfaces (Jejunum, ileum, colon)

Production of **cytotoxins**

Invasion and bacteremia are possible

How can we diagnose *Campylobacter*?

Cultures (conditions of growth differ from other enterobacteria; elective media; 42°C)

Presumptive identification can be made \~48 hours

How can we treat *Campylobacter*?

Azithromycin for severe diarrhea

Fluid/electrolyte replacement

Fluoroquinolone for invasive infection

*Vibrio cholerae*

Comma shaped Gram - bacterium

Acute infection of GI tract (Cholera)

Communities w/ inadequate drinking water & sewage disposal

Free-living bacterium in fresh water; transmitted via contaminated food (shellfish)

Characterized by epidemics and pandemics

What serogroups of *vibrio cholerae* cause epidemic cholera?

O1 & O139

Serogroup O1 has what two biotypes?

El Tor biotype

Classical biotype 

El Tor biotype

Causes mild diarrhea

Higher ratios of carriers

Serogroup O139

Originates from El Tor biotype

New capsular antigen; selective advantage where population is immune to O1 strains

Cholera toxin

Vibrio pathogenicity islands carry genes for bacteriophage carrying toxin

Permits infection by bacteriophage

Causes cholera symptoms

A subunit (activate adenylate cyclase → increases cAMP → Cl secretion & secretory diarrhea) & B subunit (binds ganglioside GM1 on eukaryotic cells)

What aids in adherence?

A. Accessory cholera enterotoxin

B. Chemotaxis proteins

C. Zonula occludens toxin

B. Chemotaxis proteins

What increases fluid secretion?

A. Accessory cholera enterotoxin

B. Chemotaxis proteins

C. Zonula occludens toxin

A. Accessory cholera enterotoxin

What loosens tight junctions to increase intestinal permeability?

A. Accessory cholera enterotoxin

B. Chemotaxis proteins

C. Zonula occludens toxin

C. Zonula occludens toxin

How does *V. cholerae* present?

Severe watery, non-bloody diarrhea (rice water stool)

Marked dehydration & electrolyte imbalance

Metabolic acidosis, hypokalemia, hypovolemic shock

Can result in cardiac shock

Untreated cholera mortality = 40-60%; treated cholera mortality =

How can we treat *V. cholerae*?

Rehydration therapy w/ fluids & electrolytes (PO or IV)

Antibiotics in severe cases

Tetracycline-resistant strains are susceptible to quinolones & macrolides

How can we prevent *V. cholerae*?

A killed, whole-cell vaccine (only effective in \~50%; protection lasts 3–6 mo)

Clean water supply

Adequate sewage disposal

*Vibrio parahemolyticus*

Halophilic

Found in estuarine, marine & coastal environments (consumption of raw seafood & fish)

Produces heat-stable cytotoxin (invades intestinal cells)

Most virulent strains produce thermostable direct hemolysin (Kanagawa hemolysin)

Most common *Vibrio* species in USA

Kanagawa hemolysin

an enterotoxin that induces chloride ion secretion in epithelial cells; increase intracellular calcium levels

How does *Vibrio parahemolyticus* present?

Self-limiting to mild, cholera-like illness

Explosive watery diarrhea

Headache, abdominal cramps, nausea, vomiting, low-grade fever

How can we diagnose vibrio?

Culture (media must be enriched w/ 1% NaCl)

Gram staining or microscopic examination of stool

Immunoassays (detection of cholera toxin or flagellar antigens)

Nucleic acid amplification tests

Shigella

Gram - rod

Causes bacillary dysentery/Shigellosis

Mass inflammation in large intestine (presence of pus & blood in stool)

Primarily a pediatric disease

Easily spread w/ poor sanitation or personal hygiene

Fecal oral route

No animal reservoir (do __**not**__ exist freely in environment)

Secrete proteins that act on epithelial cells → attaches & invades mucosal epithelium in distal ileum & colon

Kawshiorkor

Protein deficiency resulting from shigellosis + malnutrition 

What are the 4 subgroups of *Shigella*?

*Shigella sonnei* (causes most infections, mild)

*Shigella flexneri* and *Shigella boydii* (causes more severe disease)

*Shigella dysenteriae* (most severe disease)

*Shigella* toxin

Similar to EHEC

Causes damage to intestinal epithelium & glomerular endothelial cells

Can lead to kidney failure (HUS)

B subunits bind to host cell glycolipid (Gb3) → allows internalization of A subunit

A subunit cleaved → A1 cleaves 28S rRNA (prevents aminoacyl-transfer RNA binding; disrupts protein synthesis)

How can we diagnose *Shigella*?

Culture & serological typing help distinguish *Shigella* from *E. coli*

How can we treat *Shigella*?

Antibiotics for severe shigellosis

Plasmid-mediated resistance is common in *Shigella*

Rehydration is crucial

Personal hygiene and proper sewage disposal are important 

*Yersinia enterocolitica*

Food-associated infections (infants)

Can multiply at refrigerator temperatures

Zoonotic pathogen (rodents, rabbits, pigs, sheep, cattle, horses, pets)

Outbreaks associated with contaminated milk

Virulence factors (Adhesin proteins, Proteins that aid in epithelial cell invasion, Enterotoxin production)

Invasion of terminal ileum; Necrosis of Peyer’s patches; Inflammation of mesenteric lymph nodes

Presentation of enterocolitis & mesenteric adenitis

What pathogens are associated with bacterial toxin-associated diarrhea?

*B. cereus*

*S. aureus* 

*C. botulinum*

*C. perfringens*

*Staphylococcus aureus*

Food-borne illness

Acts on CNS

Implicated in autoimmune dysregulation (Pathogenesis of IBD)

Bacteria grow at room temp and release toxin (heat kills bacteria but __**NOT**__  toxin)

Toxin detected by latex agglutination assay

Enterotoxins – superantigens (bind MHC class II molecules → T cell stimulation)

Infiltration of neutrophils into epithelium & underlying lamina propria

Loss of brush border in jejunum

What subtype of S. aureus enterotoxin is most commonly associated with food poisoning?

A. Subtype A

B. Subtype B

C. Subtype C/D

A. Subtype A

What subtype of S. aureus enterotoxin causes staphylococcal pseudomembranous enterocolitis?

A. Subtype A

B. Subtype B

C. Subtype C/D

B. Subtype B

What subtype of S. aureus enterotoxins are often found in contaminated milk products?

A. Subtype A

B. Subtype B

C. Subtype C/D

C. Subtype C/D 

*Clostridium botulinum*

Exotoxin

Seven major botulinum neurotoxins (A-G) (4 are associated w/ human disease (A, B, E, and F))

Toxins not destroyed by digestive enzymes

Ingested in food; toxin can be produced in gut after consumption

Absorbed into the bloodstream to reach peripheral nerve synapses

Botulism is characterized by what?

by symmetrical descending flaccid muscle paralysis

Starts in cranial nerves → blurred vision, difficulty swallowing, slurred speech

Respiratory & cardiac muscles affected 

What is the MOA of botulism toxin?

B protects A → A subunit inactivates proteins that regulate release of ACh → Block neurotransmission at peripheral cholinergic synapses → Flaccid paralysis

Recovery depends on regeneration of nerve endings

Food-borne botulism

Produced by ingested foods, typically from home-canned foods 

Infant botulism

Most common form; associated w/ feeding honey to babies

Wound botulism

Implanted into a wound during injury

How can we diagnose *C. botulinum*?

Demonstrate presence of toxin in clinical specimens or food

Culture of bacteria

Bioassays are used if serum is available

Culture of feces or wound exudate

Toxin detection by PCR or ELISA

How can we treat *C. botulinum*?

Polyvalent antitoxin recommended 

Mechanical ventilation may be necessary

IV or nasogastric nutritional support

Antibiotics for 2º infection

How can we prevent *C. botulinum*?

Prevention of germination by spores in food by maintaining food at an acid pH, storing food at

*Clostridium perfringens*

Gram +

**Enterotoxin** – enhanced activity when exposed to trypsin

Consumption of contaminated meat; associated with pig feasts

Can occur in people released from POW camps

What are the 4 “major lethal” toxins produced by *Clostridium perfringens*?

Alpha, Beta, Epsilon, Iota

What toxins produced by *Clostridium perfringens* causes hemolysis, increased vascular permeability, and bleeding?

A. Alpha

B. Beta

C. Epsilon

D. Iota

A. Alpha 

What toxins produced by *Clostridium perfringens* causes intestinal stasis, loss of mucosa, formation of necrotic lesions?

A. Alpha 

B. Beta 

C. Epsilon 

D. Iota

B. Beta 

What toxins produced by *Clostridium perfringens* causes protoxin, activated by trypsin, increases permeability in the GI wall?

A. Alpha 

B. Beta 

C. Epsilon 

D. Iota

C. Epsilon 

What toxins produced by *Clostridium perfringens* causes necrotic activity, increases vascular permeability?

A. Alpha 

B. Beta 

C. Epsilon 

D. Iota

D. Iota

How can we diagnose *Clostridium perfringens*?

Grown on routine laboratory media (enterotoxin confirmed by latex agglutination assay)

ELISA and PCR detection are more sensitive tests

How can we prevent *Clostridium perfringens*?

Thoroughly reheating food, avoid overcooking

*Bacillus cereus*

Gram +, spore former (spores & vegetative cells contaminate many foods)

Infection can be diarrhea from production of enterotoxin in gut or vomiting due to ingestion of enterotoxin in food

Vegetative cells secrete enterotoxin in small intestine causing diarrheal disease

Emetic toxin produced in food products & ingested preformed